Expression and Localization of Endothelin Receptors: Implications for the Involvement of Peripheral Glia in Nociception

Abstract

The endothelins (ETs) are peptides that have a diverse array of functions mediated by two receptor subtypes, the endothelin A receptor (ET A R) and the endothelin B receptor (ET B R). Pharmacological studies have suggested that in peripheral tissues, ET A R expression may play a role in signaling acute or neuropathic pain, whereas ET B R expression may be involved in the transmission of chronic inflammatory pain. To begin to define the mechanisms by which ET can drive nociceptive signaling, autoradiography and immunohistochemistry were used to examine the distribution of ET A R and ET B R in dorsal root ganglia (DRG) and peripheral nerve of the rat, rabbit, and monkey. In DRG and peripheral nerve, ET A R-immunoreactivity was present in a subset of small-sized peptidergic and nonpeptidergic sensory neurons and their axons and to a lesser extent in a subset of medium-sized sensory neurons. However, ET B R-immunoreactivity was not seen in DRG neurons or axons but rather in DRG satellite cells and nonmyelinating ensheathing Schwann cells. Thus, when ETs are released in peripheral tissues, they could act directly on ET A R-expressing sensory neurons and on ET B R-expressing DRG satellite cells or nonmyelinating Schwann cells. These data indicate that ETs can have direct, nociceptive effects on the peripheral sensory nervous system and that peripheral glia may be directly involved in signaling nociceptive events in peripheral tissues.

Satellite glial cells in sensory ganglia: from form to function

“…As ET receptor blockers were found to alleviate acute and chronic pain in several animal models, it was suggested that ETs have nociceptive effects [34,53]. Pomonis et al [135] investigated the distribution of ET receptors in DRG and found that only SGCs and non-myelinating Schwann cells expressed ET B receptors, whereas neurons expressed ET A receptors (see also Ref. [82]).…”

“…[82]). On the basis of evidence that ET B -deficient mice show reduced inflammatory response [58], it was proposed that SGCs may have a role in the transmission of pain signals [135]. Although based on indirect evidence, this intriguing idea is clearly worth pursuing.…”

Targeting Bone Metastasis in Prostate Cancer with Endothelin Receptor Antagonists

“…ET-1 is found in high concentrations in dorsal root ganglion neurons and ET A receptors are found on small-to medium-sized root ganglion neurons and their axons (25). ET-1 enhances pain states in various models of acute chemicaland inflammation-induced pain and in chronic pain types such as neuropathic pain, where selective ET A inhibition shows preclinical efficacy (26).…”

Therapeutic Effects of Endothelin-A Receptor Antagonist on Bladder Overactivity in Rats with Chronic Spinal Cord Injury

“…11 A recent study by Ukai et al reported that YM598, another selective ET A receptor antagonist, reduced NVCs in BOO rats. 13 Because NVCs in BOO rats are not affected by the treatment with the C-fiber neurotoxin resiniferatoxin, 13 the emergence of bladder overactivity in this model is thought to be primarily due to myogenic changes, rather than neurogenic changes in C-fibers. Thus, it seems that the suppressive effect of ET A receptor antagonists or ECE inhibitors on BOO-induced NVCs is induced by inhibition of smooth muscle activity, which was enhanced by upregulated ET mechanisms in the obstructed bladder.…”